Mass spectrometry (MS) is an accepted analytical technique for determining the molecular weight and chemical structure of an analyte of interest. Generally, a determination is made by ionizing an analyte, and analyzing the movement of the ions with respect to predetermined electric and/or magnetic fields in a mass spectrometer. Prior methods of producing the analyte ions such as electron impact ionization, chemical ionization, and photo-ionization are typically useful only for molecules with a molecular weight of about a few hundred daltons or less.
The production of intact gas phase ions from compounds dissolved in solution has been a topic of considerable attention for some time, particularly in liquid chromatography-mass spectrometry..sup.1 Typically, the ion production process has been problematic for labile and/or high molecular weight compounds because, in many cases, the energy input to facilitate a phase change from liquid to the gas resulted in chemical reactions, rearrangements or degradation of the analyte of interest. Many compounds separated with liquid chromatography fall into this category. In recent years electrospray (ES) and electrohydrodynamic processes (EHD) have successfully demonstrated capabilities for ion production with both labile and high molecular weight compounds..sup.2-6 The terms electrospray and electrohydrodynamic are sometimes used interchangeably. For the present discussion we will refer to both processes as electrospray and restrict our definition to sprays in which conical deformation of the liquid occurs as a result of high electrical potential. This is referred to as the cone-jet mode of electrospray.
In general, ES involves introducing an analyte into a capillary tube attached to an open-ended needle (e.g., a small bore syringe needle) within an ES chamber. The analyte can be introduced by pumping or electro-osmotic flow. When the needle is electrically charged, the analyte is released as a fine spray of highly charged droplets (i.e. a cone-jet) that is generally desolvated to produce an ion beam suitable for MS.
The mechanism of ion production in ES has been the subject of considerable debate over the years..sup.7 The characteristic geometry of ES aerosol and ion generators is the simple cone-jet.sup.8 as seen in FIG. 1. We can summarize the process of electrospray by describing each part of the spray as labeled. A conducting liquid usually emerges from a capillary tube held at high electrical potential (Region A). The liquid accelerates toward a counterelectrode and assumes the characteristic conical geometry (Region B). At the apex of the cone, a high velocity jet emerges (Region C) which subsequently breaks into highly charged droplets (Region D). The highly charged droplets in Region D are generally evaporated with dry gas.sup.5 or heat.sup.9 to produce further breakup of the liquid and formation of gas phase ionic species. In some instances ions are emitted directly from the apex of the cone instead of a jet, particularly with liquid metal emittors..sup.10 Cone-jet aerosol sources have been utilized for a number of applications; including, mass spectrometry sample introduction and ionization,.sup.5,11 particle generation,.sup.12 and thruster technology,.sup.13 and liquid metal ion sources..sup.10 The operation of cone-jet source of aerosols has been demonstrated at atmospheric.sup.14-17 and at reduced pressure..sup.10,18
The production of ions from an ES source has demonstrated extremely good applicability for compounds that are labile and/or high molecular weight. ES is suitable for interfacing with analytical separation techniques such as liquid chromatography (LC), e.g., high performance liquid chromatography (HPLC); and capillary zone electrophoresis (CZE).sup.26. Typically ES ion sources are operated at atmospheric pressure because of the efficient heat transfer at these pressures to the charged droplets which results in the evaporation of the primary droplets and concomitantly causes efficient ion production. Unfortunately, at atmospheric pressure only a fraction of the ions produced are actually sampled into the low pressure detectors because of the difficulty of focusing and sampling ions through small sampling apertures to reduced pressures. Larger apertures are sometimes used to improve sampling efficiencies; however, these require more costly and/or higher capacity pumping on the vacuum system to maintain acceptable detector operating pressures. Another limitation of atmospheric pressure ES operation is the threshold of electrical discharge across the gap between the high electrical potential capillary and the counterelectrode. This threshold is generally a function of capillary and counterelectrode spacing and geometry, surrounding gas composition, and pressure. The operating voltages are limited by the discharge threshold due to partial or complete degradation of the electrospray process during an electrical discharge. Discharges generally present a greater limitation while operating atmospheric pressure ES sources in the negative ion mode..sup.19,20
The operation of ES processes at reduced pressures has allowed scientists to reduce the total gas load on the vacuum system. The operating pressure must be sufficiently low to prevent electrical discharge..sup.21 Experimental results with ES at low pressure have demonstrated (1) instability of the liquid cone-jet resulting in the formation of multiple swirling cone-jets; (2) instability in the directionality of the resulting liquid jet; (3) freezing and (4) boiling of the liquid cone at the end of the capillary; (5) a high degree of solvent clustering of the ions leaving the electrospray cone; and (6) gas phase ions possessing a wide spread in kinetic energy making the collection and focusing of the ions difficult..sup.2-4 6,18,21 Solvent clustering, along with the divergence of the droplets from the axis of the tip of the liquid cone, freezing and boiling of the liquid cone and instability of the electrospray cone have made ion detection in the low pressure mode of operation irreproducible and difficult to interpret.
Practitioners of EHD minimize the problem of freezing and boiling by dissolving their analyte in a non-volatile solvent, such as glycerine, and introducing the sample into a vacuum chamber at reduced flow rates (nanoliters/min). Some low pressure ES devices included various lenses for controlling the ions (not droplets) downstream from ES needle..sup.3,46,18 Prior related art can be divided into four (4) groups:
1. low pressure electrospray without a focusing means for sampling into a low pressure detector (such as, references 4 and 23); PA1 2. low pressure electrospray with a focusing means for directing the aerosol into low pressure detectors (such as, references 3 and 6); PA1 3. low pressure electrospray with a focusing means for directing aerosol into a high pressure declustering region (such as, reference 6); and PA1 4. low pressure electrospray without a focusing means and sampling the aerosol into a high pressure ionization region (such as, reference 22).
The art of Mahoney and coworkers.sup.6 addresses declustering downstream from the spray but does not effectively deal with the evaporation of droplets produced at low pressure.
Platzer.sup.22 addresses the problem of solvent declustering and wide kinetic energy spread at low pressures by directly spraying from low pressures through a heated tube into a higher pressure ionization region. The art of Platzer fails to address the inherent instability of the primary electrospray process, freezing and boiling in a vacuum; and the wide angular and spatial dispersion of the spray. The primary outcome of failing to address the low pressure spray stability will result in significant losses of analyte and droplets on the walls of their first chamber and the heated transfer tube. Although, they may collect some of the spray through the tube by virtue of large cross sectional diameters, they will still have an irreproducible and unstable signal resulting from the unstable spray processes.
However, significant disadvantages are encountered when ES is used to make a cone-jet at or near atmospheric pressure. For example, the analyte ions of the cone-jet are often exposed to pressure reduction as the ions are desolvated. Transport of the analyte ions usually occurs with a high gas load interfacing system which, even when working optimally, causes a substantial loss in signal strength, sometimes at a level of about four orders of magnitude. Large sampling apertures are sometimes used to improve sampling efficiencies; however these apertures require more costly and/or higher capacity vacuum pumping systems to maintain acceptable mass spectrometer operating pressures.
Another limitation of atmospheric pressure ES is the presence of an electrical discharge threshold across a gap between the needle and a counterelectrode. An electrical discharge typically causes degradation of the cone-jet in the ES chamber. The electrical discharge threshold limits ES operating voltages at atmospheric pressure, and it is affected by the spacing and geometry of the needle and counterelectrode, as well as the composition and pressure of the surrounding gas.sup.2. Electrical discharges present even greater limitations if the highly charged droplets are made in the negative ion mode.sup.20. Further, such discharges can adversely limit the choice of gas to be used in the ES chamber.sup.27.
The disadvantages inherent in atmospheric mode ES are relevant when ES is interfaced with LC/MS, or CZE/MS systems such as disclosed in U.S. Pat. Nos. 4,842,701 and 4,885,076 to Smith et al.
Another ES mode of operation involves producing the cone-jet in an evacuated ES chamber. For example, U.K. Patent No. 1,246,709 to Hazelby and Preston discloses spraying charged droplets into an evacuated ES chamber and then heating the droplets with an optical source. A related method has been disclosed in U.S. Pat. No. 4,160,161 to Horton.
However, significant disadvantages are encountered when a cone-jet is made in an evacuated chamber. For example, the chance of electrical discharges and distortions is increased, in part because the cone-jet can make contact with the ES chamber wall. Additionally, making the cone-jet in an evacuated chamber can often result in undesirable solvent clustering.sup.3&4. Also, disadvantageously, aerosol pulsations, freezing, boiling, non-reproducible MS spectra, ion clusters, and wide ion distributions can result.
Cone-jets produced by most prior ES techniques include solvated analyte ions, making them unsuitable for MS. Desolvation of the analyte ions has been achieved by a variety of methods. For example, one ES mode of operation uses heated gases, capillaries and the like to cause desolvation at or near atmospheric pressure (U.S. Pat. Nos. 5,105,845 to Allen and Vestal; 4,531,056 to Labowsky et al.; and 4,977,320 to Chowdhury et al.), whereas another ES mode uses solvent-depleted gas for desolvation (i.e. "countercurrent" gas method, see U.S. Pat. No. 4,209,696 to Fite). Other methods use pressure reduction and heat to remove solvent (U.S. Pat. No. 5,105,845 to Allen and Vestal; U.S. Pat. No. 5,105,845 to Horton), while still other methods desolvate analyte ions by combining pressure reduction and a flow of heated gas (U.S. Pat. No. 4,531,056 to Labowsky et al.; U.K. Patent No. 1,246,709 to Hazelby and Preston). However, such methods generally cause high gas loads, resulting in low efficiency ion transfer to the mass spectrometer.
Additionally, the use of a countercurrent gas at or near atmospheric pressure (e.g., see U.S. Pat. No. 4,209,696 to Fite) increases the complexity of analysis. For example, gas flow rate and temperature must often be optimized for each analyte and solvent of interest, making the technique time-consuming when multiple analytes and solvents are used.
The object of the current invention is to overcome the aforementioned limitations of both atmospheric pressure and low pressure operations of electrospray.